Diabetes and hypertension are major risk factors for developing chronic kidney diseases (CKD). Despite intense research, the mechanisms that underlie the pathways to renal hypoxia and CKD remain poorly under- stood. That dif?culty may be attributable to the complex interplay among the millions of renal tubules and vessels that forms the basis for the integrative function of the kidney but that remains to be fully characterized. We have previously developed computational models of the rat kidney that represent the complex interactions, and we aim to extend those models and to conduct simulations that will provide insights into the kidney in health and disease. The proposed project includes (I) To develop a detailed and multiscale computational model of integrative rat kidney function, and to use that model to examine key determinants of kidney function and medullary oxygenation. Simulations of functional knockout and nephron loss will be conducted to determine: What are the necessary nephron structures and functions that must be preserved or should be inhibited to maintain or increase oxygen balance in the vulnerable outer medulla, while maintaining overall key kidney functions? (II) To simulate and gain insights into the pathophysiology and therapeutics of renal hypoxia in hypertension and diabetes. Hypertension and diabetes induce unique effects on the tubular system that increases kidney oxygen consumption. Model simulations will be conducted to investigate factors that impact intrarenal oxygen tension (PO2), particularly in the vulnerable outer medulla, including hypertension-induced shift in Na+ transport to the more distal and less ef?cient nephron segments, elevated oxidative stress, diabetes-induced hyper?ltration and tubular hypertrophy and hyper-reabsorption. We will simulate and investigate the effectiveness of current and novel therapeutic treatments and seek to answer questions like: How can one increase Na+ excretion in hypertension while limiting effects on other kidney functions and preserve medullary oxygenation? In diabetes, what is the in?uence of inhibiting Na+-glucose cotransport on renal NaCl transport and O2 requirement? To what extent do pressure reduction maneuvers increase medullary PO2 and protect the kidney? (III) To conduct experimental studies to assess the renal effects of sodium-glucose cotransporter (SGLT) inhibition. Inhibiting glucose reabsorption along the proximal tubule via SGLT2 is a novel approach for lower blood glucose level in diabetes. We will perform experiments on mice to determine: Does SGLT2 inhibition enhance Na+ transport of vulnerable downstream nephron segments and increase outer medullary hypoxia? Is there any bene?t in the additional inhibition of SGLT1 along the late proximal tubule, which limits Na+ glucose reabsorption along that segment, but may further increase thick ascending limb Na+ transport? Does SGLT inhibition facilitate ischemia- reperfusion injury or impair the recovery? At the completion of these studies, we would have gained new insights into the key determinants of kidney function and medullary oxygenation in the normal kidney, and determined their potential relevance in the pathways from hypertension and diabetes to CKD.